Project Summary/Abstract Traumatic brain injury (TBI) is a significant health problem and a potentially catastrophic debilitating medical emergency with a poor prognosis and the possibility of long-term disability. Blast-related and closed-head injuries constitute the majority of TBIs occurring in the combat zone. Recent studies demonstrate that diffuse axonal injury (DAI) is the most common pathologic feature largely accounting for the clinical manifestations of TBI. Thus, future advancements in the diagnosis and treatment of TBI depend on our understanding of temporal axonal pathophysiology of DAI and its role in patient outcome. However, several factors have limited our understanding of the pathology and functional implications of DAI: (1) DAI is extremely difficult to detect noninvasively; (2) it develops over a course of hours to days, even months, after injury; (3) DAI is difficult to study because it involves multiple types of neurons and is diffuse and multifocal, appearing throughout the deep and subcortical white matter. This research project will take advantage of the optic nerve system to explore the hypothesis that an innovative neuroprotective and regenerative approach is effective on minimizing axonal damage and improving the morphological and functional recovery after CNS trauma. The optic nerve, which conveys visual information from the eye to brain, contains axons originated from a single neuronal population- retinal ganglion cells. Its peripheral location makes it an unusually accessible both structurally and functionally. Optic nerve injury that creates axonal damage morphologically identical to that seen in the brain offers a well-defined anatomical system that obviates many of the difficulties associated with experiments on the brain. Moreover, using the advanced mouse genetic technology, successful full-length optic nerve regeneration from the eye to the brain has been achieved in postnatal mice. The study demonstrates the feasibility of limiting DAI following TBI and treating brain trauma. To elucidate the pathology and mechanisms associated with axonal damage, especially DAI resulted from blast force-induced TBI (bTBI), and to develop new treatment, this research plan proposes 3 specific aims: Aim 1 is proposed to define the pathology and mechanisms of axonal damage induced by trauma and/or TBI. Aim 2 will use advanced mouse genetic technology to elucidate the molecular signals leading to the chronic axonal damage. Aim 3 will evaluate a novel neuroprotective and regenerative approach to minimize axonal damage resulted from trauma. Quantification of neuron and axon damage will be carried out using the standard protocols of immunohistochemistry and molecular and biochemical assays that have been well-established. If the hypothesis is proven valid, an innovative technology that has strong implications for translation into clinical practice could be developed in the near future.